Ether derivatives of bicyclic heteroaryls

Abstract

The invention relates to compounds of formula I, wherein the substituents are as defined in the specification; to processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; such compounds as a medicament; such compounds for the treatment of a proliferative disease.

1 . A compound according to formula I, 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         A 1  represents N, A 2  represents C, A 3  represents N, and A 4  represents CH; or 
         A 1  represents CH, A 2  represents N, A 3  represents C, and A 4  represents N; 
         R 1a  and R 1b  together with the atoms to which they are attached form a 3-12 membered monocyclic or bicyclic, saturated or partly saturated, heterocyclyl having 1-3 oxygen atoms, 0-3 nitrogen atoms, and 0-2 sulfur atoms; said heterocyclyl being optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7  alkyl)amino; and 
         R 1c  represents hydrogen or C 1-7 alkyl; or 
         R 1a  and R 1b  and R 1c  together with the atoms to which they are attached form a 6-12 membered bicyclic, saturated or partly saturated, heterocyclyl, having 1-3 oxygen atoms, 0-3 nitrogen atoms, and 0-2 sulfur atoms; said heterocyclyl being optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7  alkyl)amino; or 
         R 1a  represents branched C 3-8  alkyl or C 3-10 cycloalkyl; 
         R 1b  represents hydrogen or C 1-7  alkyl; and 
         R 1c  represents hydrogen or C 1-7  alkyl; 
         m represents 1 or 2; 
         n represents 1 or 2; 
         A 5 -R 2  represents N—R 2 , NC(H)R 2 R 3 , CR 2 R 3 , or CR 3 —CH 2 —R 2 ; 
         R 3  represents hydrogen, C 1-7 alkyl, or hydroxy; and 
         R 2  represents a 3-12 membered monocyclic or bicyclic, saturated or partly saturated, heterocyclyl having 1-3 nitrogen atoms, 0-3 oxygen atoms, and 0-3 sulfur atoms; said heterocyclyl being optionally substituted with one to four substituents each independently selected from the group consisting of halo; cyano; oxo; hydroxy; carboxy; amino; nitro; SO 2 R 4 ; COR 5 ; C 1-7 alkyl; C 1-7 alkyl halo optionally substituted with one hydroxy; C 1-7 alkoxy; hydroxy-C 1-7 alkyl; piperazinyl C 1-3 alkyl; aminocarbonyl; C 1-7 alkylaminocarbonyl; and di(C 1-7 alkyl)aminocarbonyl; or 
         R 2  represents OH; SH; C 1-7 alkoxy; C 1-7 alkylthio; C 1-7  alkyl optionally substituted with one SO 2 R 4  or NHR 4  group; NHR 5 ; NHC(O)R 5 ; NHC(O)NHR 5 ; NHC(O)OR 5 ; SO 2 R 4 ; NHSO 2 R 5 ; NHNHC(O)R 4 ; imidazolyl optionally substituted with one methyl, CH 2 OH or C(O)OR 7 ; tetrazolyl optionaly substituted with one methyl; or oxazoly; or 
         R 2  and R 3  together with 
       
       
         
           
           
               
               
           
         
       
       the moiety form 5,7-dioxa-spiro[3.4]octanyl, 5-oxa-7-aza-spiro[3.4]octanyl, or 5-oxa-8-aza-spiro[3.5]nonanyl, each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: halo; cyano; oxo; hydroxy; amino; nitro; C 1-7  alkyl; C 1-7 alkoxy; hydroxy-C 1-7 alkyl; aminocarbonyl; C 1-7 alkylaminocarbonyl; and di(C 1-7 alkyl)aminocarbonyl;
 R 4  represents hydrogen or C 1-7  alkyl; and 
 R 5  represents hydrogen; C 1-7  alkyl; hydroxy-C 1-7 alkyl; C 1-7 alkyl; halo; C 3-7  cycloalkyl optionally substituted with one or two C 1-3  alkyl groups; piperazinly optionally substituted with one C 1-3  alkyl; tetrahydropyranyl; pyridinyl optionally substituted with one methyl or cyano. 
 
     
     
         2 . The compound according to  claim 1 , depicted by the formula I-1 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein
 R 1a  and R 1b  together with the atoms to which they are attached form a 3-12 membered monocyclic, saturated heterocyclyl, containing 1-3 oxygen atoms,
 said heterocyclyl being optionally substituted, with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7 alkyl)amino; and 
   R 1c  represents hydrogen; or   R 1a R 1b  and R 1c  together with the atoms to which they are attached form a bicyclic heterocyclyl, said heterocyclyl being selected from the following moieties:   
       
         
           
           
               
               
           
         
         
           said heterocyclyl being bound to the molecule via the marked carbon atom, and 
           said heterocyclyl being optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7 alkyl)amino; or 
         
         R 1a  represents branched C 3-8 alkyl or C 3-10 cycloalkyl, 
         R 1b  represents hydrogen and 
         R 1c  represents hydrogen. 
       
     
     
         4 . The compound according to  claim 3 , wherein
 R 1a  and R 1b  together with the atoms to which they are attached form tetrahydrofuryl or tetrahydro-2H-pyranyl optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7 alkyl)amino; and   R 1c  represents hydrogen; or R 1a , R 1b  and R 1c  together with the atoms to which they are attached form 8-oxabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, or d 9 -7-oxabicyclo[2.2.1]heptanyl optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7 alkyl)amino; or   R 1a  represents branched C 3-8 alkyl or C 3-10 cycloalkyl,   R 1b  represents hydrogen; and   R 1c  represents hydrogen.   
     
     
         5 . The compound according to  claim 1 , wherein A 5 -R 2  represents CHR 2  or CH—CH 2 —R 2 . 
     
     
         6 . The compound according to  claim 1 , wherein m represents 1. 
     
     
         7 . The compound according to  claim 1 , wherein m and n represent 2. 
     
     
         8 . The compound according to  claim 1 , wherein m and n represent 1. 
     
     
         9 . The compound according to  claim 5 , wherein R 2  is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl, each optionally substituted with one to four substituents each independently selected from the group consisting of halo; cyano; oxo; hydroxy;
 carboxy; amino; nitro; SO 2 R 4 ; COR 5 ; C 1-7 alkyl; C 1-7 alkyl halo optionally substituted with one hydroxy; C 1-7 alkoxy; hydroxy-C 1-7 alkyl; piperazinyl C 1-3 alkyl; aminocarbonyl; C 1-7 alkylaminocarbonyl; and di(C 1-7 alkyl)aminocarbonyl.   
     
     
         10 . The compound according to  claim 9 , wherein R 2  is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl, each optionally substituted with one or two substituents each independently selected from the group consisting of C 1-3 alkyl; fluoro; hydroxy; oxo; carboxy; C 1-3 alkoxy carbonyl; C 1-3 alkyl halo optionally substituted with one hydroxy; hydroxy-C 1-3 alkyl; piperazinyl C 1-3 alkyl; aminocarbonyl; C 1-3 alkylaminocarbonyl; methoxycarbonyl; methylsulfonyl; and methylcarboxy. 
     
     
         11 . The compound according to  claim 10 , wherein R 2  is selected from the group consisting of the following moieties: 
       
         
           
           
               
               
           
         
         in which the marked atom is bound to A 5 . 
       
     
     
         12 . The compound according to  claim 1 , wherein A 5 -R 2  represents CR 2 R 3 . 
     
     
         13 . The compound according to  claim 1 , of formula I-7 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  and R 1b  together with the atoms to which they are attached form a tetrahydrofuranyl ring optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino; C 1-7 alkylamino; and di(C 1-7 alkyl)amino; and 
         R 1c  represents hydrogen or C 1-7 alkyl; or 
         R 1a  and R 1b  and R 1c  together with the atoms to which they are attached form 7-oxabicyclo[2.2.1]heptanyl or d 9 -7-oxabicyclo[2.2.1]heptanyl either being optionally substituted with one to three substituents each independently selected from the group consisting of C 1-7 alkyl; C 1-7 alkoxy; halo; cyano; hydroxy; oxo; nitro; amino C 1-7 alkylamino, and di(C 1-7 alkyl)amino; 
         A 5 -R 2  represents CR 2 R 3  or CR 3 —CH 2 —R 2 ; 
         R 3  represents hydrogen, C 1-7 alkyl, or hydroxy; and 
         R 2  represents piperazinyl, thiomorpholinyl, or 2-thia-5-aza-bicyclo[2.2.1]heptanyl optionally substituted with one to four substituents each independently selected from the group consisting of halo; cyano; oxo; hydroxy; carboxy; amino; nitro; SO 2 R 4 ; 
         COR 5 ; C 1-7 alkyl; C 1-7 alkyl halo optionally substituted with one hydroxy; C 1-7 alkoxy; 
         hydroxy-C 1-7 alkyl; piperazinly C 1-3  alkyl; aminocarbonyl; C 1-7 alkylaminocarbonyl; and 
         di(C 1-7 alkyl)aminocarbonyl; or 
         R 2  represents OH; or 
         R 2  and R 3  together with the 
       
       
         
           
           
               
               
           
         
       
       moiety form 5-oxa-7-aza-spiro[3.4]octanyl optionally substituted with one to three substituents each independently selected from the group consisting of: halo; cyano; oxo; hydroxy; amino; nitro; C 1-7 alkyl; C 1-7 alkoxy; hydroxy-C 1-7 alkyl; aminocarbonyl; C 1-7 alkylaminocarbonyl; and di(C 1-7 alkyl)aminocarbonyl;
 R 4  represents hydrogen or C 1-7  alkyl; and 
 R 5  represents hydrogen; C 1-7 alkyl; hydroxy-C 1-7 alkyl; C 1-7  alkyl halo; C 3-7  cycloalkyl optionally substituted with one or two C 1-3  alkyl groups; piperazinly optionally substituted with one C 1-3  alkyl; tetrahydropyranyl; or pyridinyl optionally substituted with one methyl or cyano. 
 
     
     
         14 . The compound according to  claim 1  which is:
 cis-7-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]cyclobutyl}-5-{3-[(2S)-tetrahydrofuran-2-ylmethoxy]phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 
 7-[3-(1,1-dioxo-1-thiomorpholin-4-ylmethyl)-cyclobutyl]-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; 
 d 2 -7-[cis-3-(1,1-dioxo-1-thiomorpholin-4-ylmethyl)-cyclobutyl]-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; 
 d 9 -7-[cis-3-(1,1-dioxo-1-thiomorpholin-4-ylmethyl)-cyclobutyl]-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; or 
 7-[cis-3-(1,1-dioxo-thiomorpholin-4-yl)-cyclobutyl]-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; or a salt thereof. 
 
     
     
         15 . The compound according to  claim 1  which is:
 (R)-1-(cis-3-{4-amino-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid amide; 
 (S)-1-(trans-3-{4-amino-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid amide; or 
 (R)-1-(trans-3-{4-amino-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-cyclobutylmethyl)-pyrrolidine-2-carboxylic acid amide; or a salt thereof. 
 
     
     
         16 . The compound according to  claim 1  which is:
 1-{4-[cis-3-(4-amino-5-{3-(S)-1-(tetrahydrofuran-2-yl)methoxy]-phenyl}-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-piperazin-1-yl}-ethanone; 
 7-[cis-3-(4-methanesulfonyl-piperazin-1-yl)-cyclobutyl]-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; 
 3-[3-(methyl-piperazin-1-yl)-cyclobutyl]-1-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine; or 
 1-[cis-4-(3-{4-Amino-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-cyclobutyl)-piperazin-1-yl]-ethanone; or a salt thereof. 
 
     
     
         17 . The compound according to  claim 1  which is:
 (3-{4-amino-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-pyrrolo[2,3-d]pyrimidin-7-yl}-cyclobutylmethyl)-carbamic acid methyl ester, or a salt thereof. 
 
     
     
         18 . The compound according to  claim 1  which is:
 (endo)-5-[3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7-[3-((1S,2S,4S)-2-oxo-2-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; 
 5-[cis-3-(7-oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7-[3-(1-oxo-thiomorpholin-4-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; or 
 5-[3-(7-Oxa-bicyclo[2.2.1]hept-1-ylmethoxy)-phenyl]-7-[cis-3-(1-oxo-thiomorpholin-4-yl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine; or a salt thereof. 
 
     
     
         19 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to  claim 1 , and one or more pharmaceutically acceptable carriers. 
     
     
         20 . A pharmaceutical combination comprising a therapeutically effective amount of a compound of formula I according to  claim 1 , and an antiproliferative agent. 
     
     
         21 - 25 . (canceled) 
     
     
         26 . A method of modulating IGF-1R activity in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I according to  claim 1 . 
     
     
         27 . A method for the treatment of an IGF-1R mediated disorder or disease comprising the step of administering to a subject a therapeutically effective amount of a compound of formula I according to  claim 1 . 
     
     
         28 . The method of  claim 27  wherein the disorder or disease is selected from the group consisting of multiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing's Sarcoma, adrenocotical carcinoma (ACC) or a solid tumor selected from osteosarcoma, melanoma, tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterine and gastrointestinal tumor. 
     
     
         29 . The method of  claim 27  wherein the disorder or disease is selected from acute lung injury and pulmonary fibrosis.